Omacetaxine mepesuccinate (SYNRIBO™) is used to treat adults with chronic or accelerated phase chronic myeloid leukemia (CML) who are no longer responding to, or who could not tolerate, two or more tyrosine kinase inhibitors. Omacetaxine mepesuccinate is a cephalotaxine ester and is a protein synthesis inhibitor. Omacetaxine mepesuccinate is typically prepared by a semi-synthetic process from cephalotaxine, an extract from the leaves of Cephalotaxus sp. While cephalotaxine accounts for approximately 50% of the mass of the crude alkaloid extract mixture from powdered leaves and stems of Cephalotaxus sp., several minor constituents have also been identified. Among these are several rare C3-ester derivatives. The ester derivatives show cytotoxic properties, but cephalotaxine itself has been found to be biologically inactive. However, the naturally occurring ester derivatives are typically attainable in only <0.1% of the plant dry weight. Certain cephalotaxus ester derivatives, namely omacetaxine mepesuccinate, are available through semisynthetic methods. The synthesis of omacetaxine mepesuccinate [aka (−)-homoharringtonine] has been achieved by semi-synthetic methods from the combination of cephalotaxine with various activated malic acid-derived precursors that make up the mepesucinate portion.
Cephalotaxine is commercially available and easily sourced, and has been the target of numerous total synthesis publications. As a result, the majority of publications and patents centers around ways to prepare the enantiopure mepesuccinate portion. Although the synthesis of both racemic and enantiopure side chain precursors have been reported as far back as the 1980s (for instance Hudlicky et al., Tetrahedron Lett., 23: 3431 (1982)), the research groups of Gin and Tietze have fashioned enantiopure side chain precursors from cyclic malic acid templates as shown below:
In the case of both groups, (2R)-malic acid (A) was cyclized to the dioxolanone scaffold B, which was treated with two equivalents of base at low temperature. The resulting dianion was treated with various allylic halides to produce the C-alkylated adducts C, which were then converted to a-alkylated malic acid monoesters D. This work with allylic halides is in itself not new, as the Self-Regeneration of Stereocenters (SRS) concept was demonstrated with this same scaffold B by Seebach and coworkers in the early 1980s (Seebach et al., Helv. Chim. Acta, 64: 2704 (1981); see also Seebach et al., Angew. Chem. Int. Ed., 35:2708 (1996)).
The Tietze group has used this chemistry to prepare homoharringtonine analogs, but not omacetaxine mepesuccinate in particular (Tietze et al., Eur. J. Org. Chem., 2965 (2005)). The Gin group has reported this chemistry for the preparation of homoharringtonine analogs (Gin et al., J. Am. Chem. Soc., 128:10370 (2006)) and specifically to prepare the side chain of omacetaxine mepesuccinate (Gin et al., Chem. Eur. J., 14:4293 (2008); U.S. Pat. No. 8,466,142). The synthetic sequence for the process as it appears in the 2008 publication and '142 Patent is as shown below:

However, such approaches are not efficient and typically require careful chromatography steps to obtain the desired isomer for treatment. Moreover, such approaches are not able to produce other bioactive members of the family.
The present invention is directed to overcoming these and other deficiencies in the art.